Various inner ear disorders, e.g. hearing loss, inner ear infectious disease or tinnitus, have attracted increased interest with the object to provide new therapies. E.g. tinnitus, the perception of sound without external acoustic stimulation, is a very common inner ear disorder. An estimated 7% to 14% of the population have talked with their physician about tinnitus, while potentially disabling tinnitus occurs in approximately 1% to 2.4% of people (Vesterarger V., British Medical Journal 314 (7082): 728-731 (1997)). Tinnitus is often associated with other hearing disorders, such as hearing loss or hyperacusis, i.e. hypersensitivity to sound (Sahley T. and Nodar R., Hearing Research (152): 43-54), and quite often originates in the inner ear.
Various pharmaceutical compounds have already been tested in animal models or in human beings for the treatment of inner ear diseases, e.g. tinnitus, such as lidocaine, gabepentin, nortryptline, melatonin, caroverine, baclofen, alprazolam, gacyclidine, 7-chlorokynurenate, or ketamine. While some of them have shown great promise, none of them is in regular clinical use, yet. One of the key obstacles to the development of effective treatments has been the fact that the inner ear is protected like the brain by a biological barrier. For systemic drug administration, relatively high doses are usually required to achieve a desired therapeutic effect in the inner ear, carrying the risk of potent side effects on the central or peripheral nervous system. Topical administration to the inner ear on the other side allows for a targeted delivery of compounds with much lower doses required, as shown by inner ear pharmacokinetic studies (Chen et al., Audiol. Neurootol. 8: 49-56 (2003)). Access to the inner ear may be achieved through a variety of middle-inner ear interface tissue structures, such as the round window membrane, the oval window/stapes footplate, the annual ligament or the endotymphatic sac/endolymphatic duct.
Topical administration of the compound to the inner ear may be accomplished by various delivery techniques. These include the use of devices to transport and/or deliver the compound in a targeted fashion to the membranes of the round or oval window, where it diffuses into the inner ear or is actively infused. Examples are otowicks (see e.g. U.S. Pat. No. 6,120,484 to Silverstein), round window catheters (see e.g. U.S. Pat. Nos. 5,421,818; 5,474,529; 5,476,446; 6,045,528; all to Arenberg, or U.S. Pat. No. 6,377,849 and its division 2002/0082554 to Lenarz), or microimplants (see e.g. WO2004/064912 by Jukarainen et al.). They further include the use of devices which are inserted into the cochlear duct or any other part of the cochlea (see e.g. U.S. Pat. No. 6,309,410 to Kuzma). Another delivery technique is transtympanic injection (sometimes also called “intratympanic injection”), whereas the medication is injected through the tympanic membrane into the middle ear typically for diffusion across the round window membrane (for a description see e.g. Light J. and Silverstein H., Current Opinion in Otolaryngology & Head and Neck Surgery (12): 378-383 (2004). It has been used in clinical practice for a long time and is a relatively minor intervention, which can be carried out in a doctor's office. For repeated injections, a middle ear ventilation tube may be inserted into the tympanic membrane, through which the medication can be administered into the middle ear space. Drug carriers that are too viscous to be injected may also be deposited across a small opening in the tympanic membrane with the aid of surgical instrument.
In order to increase the therapeutic efficacy of pharmaceutical compounds for inner ear therapy, particular formulations with gels, foams or fibrins or other drug carriers can be used. They may provide for the controlled release of the drug over an extended period of time such as hours, days or weeks, improve its diffusion into the inner ear by increasing the permeability of the middle-inner ear interface tissue structure or by keeping the formulation in continuous contact with such structure. This compares favourably to the administration of the pharmaceutical compound in a solution, where multiple injections might be required, drug percolation back into the ear canal or significant loss down the Eustachian tube could result, and continuous contact with the middle-inner ear interface tissue structure might be difficult or impossible to achieve. Ideally, the drug carrier is biocompatible as well as biodegradable, in which case there is no need for subsequent removal.
The diffusion of pharmaceutical compounds across middle-inner ear interface tissue structures, in particular the round window membrane, depends on a variety of factors, such as molecular weight, concentration, liposolubility, electrical charge, and thickness of the membrane (Goycoolea M. and Lundman L., Microscopy Research and Technique 36: 201-211 (1997)). In the absence of experimental data obtained in vivo or with membrane tissue, the capacity to cross middle-inner ear interface tissue structures and thus the suitability of any pharmaceutical compound or formulation for topical administration to the inner ear remains unknown.
Selivanova at al., Laryngo-Rhino-Otol (82): 235-239 (2003) demonstrate in vivo that hyaluronic acid increases the permeability of the round window membrane and that the test substance lidocaine is thus more rapidly diffused into the inner ear and produces a larger effect. Chandrasekhar S., Otology & Neurotology (22): 18-23 (2001) show in vivo that transtympanic injection of dexamethasone with histamine results in higher concentrations of this steroid in the perilymph of the inner ear than if administered without.
There exists vast literature concerning (topical) administration of pharmaceutical compounds to treat inner ear diseases. Steroids and aminoglycosides have been administered locally to the inner ear in clinical practice for quite some time (see e.g. Hoffer et al., Otolaryngologic Clinics of North America (37): 1053-1060 (2004)). Sakata et al., International Tinnitus Journal (2): 129-135 (1996), describe the intratympanic infusion of dexamethasone into the tympanic cavity of human beings. Hoffer et al., Otolaryngologic Clinics of North America (36): 353-358 (2003), describe transtympanic injections of methylprednisolone solutions for the treatment of tinnitus following noise trauma or sudden deafness. In all these cases, the drug compounds were applied in solutions. However, there is less known about topical treatment of inner ear diseases with other formulations.
WO1997/38698 by Manning et al. teaches the use of biocompatible polymers to deliver pharmaceutical compounds to the inner ear for treating middle and inner ear diseases, e.g. Meniere's disease or viral and bacterial infection diseases. Experimental in vitro release data is shown for a hyaluronic acid formulation with gentamicin.
WO2004/022069 by Puel et al. describes the delivery of neuromodulatory agents, in particular the NMDA antagonists gacyclidine, D-AP5, MK 801 and 7-chlorokynurenate, with a variety of formulations, including drug carriers such as gelfoam, hyaluronic acid, or fibrin glue for the treatment of various inner ear diseases. Moreover, a plurality of alternative insertion methods for administration of the formulation into the middle ear is described by WO2004/022069.
In the light of the literature above and the disadvantages involved with many of the pharmaceutical compositions used so far for topical administration there is a need for other pharmaceutical compositions appropriate for topical treatment of inner ear disorders, which can be easily injected into the middle ear, release the drug over an extended period of time, and allow for a high percentage of the drug to be delivered into the inner ear.